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In contrast to earlier approaches that focused mainly on a specific group of approved drugs (e purchase ofloxacin 200mg with mastercard. In studying an investigational drug as the interacting (inhibiting or inducing) drug cheap 400mg ofloxacin free shipping, the choice of substrates (approved drugs) for initial 674 Huang et al order 200 mg ofloxacin free shipping. In testing inhibition order ofloxacin 200 mg mastercard, the substrate selected should generally be one whose phar- macokinetics are markedly altered by coadministration of known specific inhibitors of the enzyme systems to assess the impact of the interacting inves- tigational drug. If the initial study shows that an investigation drug either inhibits or induces metabolism, further studies using less sensitive substrates, based on the likelihood of coadministration, may be useful. In testing an inves- tigational drug for the possibility that its metabolism is inhibited or induced (i. The choice of interacting drug can then be based on known, important inhibitors of the pathway under investigation. If the study results are negative, then absence of a clinically important drug-drug interaction for the metabolic path- way would have been demonstrated. If the clinical study of the strong, specific inhibitor/inducer is positive, it should generally be determined in further clinical studies whether there is an interaction between the test drug and less potent specific inhibitors or inducers. Use of the drug with grapefruit juice may call for caution depending on the drug’s exposure-response relationship (23). John’s wort may be listed in the labeling along with other known inducers, such as rifampin, rifabutin, rifapentin, dexamethasone, phenytoin, carbamazepine, or phenobarbital, as possibly decreasing plasma levels. When the above study shows significant interaction, further evaluation with weaker inhibitors may be necessary. In testing an investigational drug for the possibility that it may be an inhibitor/ inducer of P-gp in vivo, digoxin or other known substrates of P-gp should be used. In testing an investigational drug for the possibility that its transport may be inhibited or induced in vivo (as a substrate of P-gp), an inhibitor of P-gp should be studied. In testing an investigational drug for the possibility that its disposition may be inhibited or induced (i. Route of Administration For an investigational agent used as either an interacting drug or substrate, the route of administration should generally be the one being studied in trials. If only oral dosage forms will be marketed, studies with an intravenous formulation are not usually necessary, although information from oral and intravenous dosings may be useful in discerning the relative contributions of alterations in absorption and/or presystemic clearance to the overall effect observed for a drug interaction. For example, the interaction studies of clarithromycin and intravenous or oral doses of midazolam enabled Gorski et al. Sometimes the use of certain routes of administration may reduce the utility of information from a study. Dose Selection For both substrate and interacting drug, testing should maximize the possibility of finding an interaction. Doses smaller than those to be used clinically may be needed for substrates on safety grounds and should provide an adequate assessment of an interaction. The differential effects of different doses of ritonavir on the plasma levels of saquinavir (18) demonstrate the dose effect of an interacting drug. In some cases, these measures may be of interest for the inhibitor or inducer as well, notably where the study is intended to assess possible interactions between both study drugs. In certain instances, an understanding of the relationship between dose, blood levels, and response may lead to a special interest in particular pharmacokinetic measures/parameters. For example, if a clinical outcome is most closely related to peak concentration (e. In certain instances, reliance on endpoints in addition to pharma- cokinetic measures/parameters may be useful. Increasingly, also, these factors can affect the regulatory decision to approve such a drug and/or how it is labeled. Section 505 of the Food Drug and Cosmetic Act requires that, for approval, a drug must be demonstrated to be both effective and safe when used as labeled. Safety is not an absolute measure but rather reflects a conclusion that the drug’s benefits outweigh its risks. Among the risks that must be considered is the presence of individuals who are at particular risk because of individual characteristics (e. It is striking that several important drugs—terfenadine, mibefradil, astemizole, and cisapride—have been removed from the market, at least partly, because of drug-drug interaction problems (28–31). The importance of both mean and between- and within- individual variability must be assessed in light of many factors. These include the toxicity of the drug (wide therapeutic range drugs may not be harmful even if their pharmacokinetics are very variable, e. In the context of a non-life-threatening condition for which numerous safe and effective alternative therapies exist, such a drug would be unlikely to be approved for marketing today. In contrast, the potential for serious toxicities due to drug interactions is not an insurmountable impediment for drugs intended to treat severe or life-threatening conditions, particularly when alternative treatments are not available. In these instances, close attention to labeling and other aspects of risk management will be needed to inform practitioners and patients about the likelihood and consequences of interactions and the ways to avoid them. Drug absorption, metabolism, and excretion, and drug-drug interaction information appears, as appropriate, in some or all of the following sections of the approved product label—Clinical Pharmacology, Contraindications, Warnings and Pre- cautions, Adverse Reactions, or Dosage and Administration (32). Certain basic An Integrated Approach to Assessing Drug-Drug Interactions 681 pharmacokinetic information is almost always included (e. Recently approved product labels have reflected the increased understanding of the pathways and consequences of drug metabolism by health care practitioners. The following section describes the appropriate location for drug metabolism and drug-drug interaction information. The role of P-gp and other transporter mechanisms and their relationship to drug-metabolizing enzymes remain to be fully understood, and the effects on P-gp-mediated transport are only beginning to be reflected in labeling at this time. It is easy to envision, however, that the role of transporters and the clinical consequences of their modulation will soon be better understood and studied so that information on these systems will appear regularly in labeling. The clinical consequences of metabolism and interactions should be placed in drug interactions, warnings and precautions, boxed warnings, contraindications, or dosage and administration sections, as appropriate. Information related to clin- ical consequences should not be included in detail in more than one section, but rather reported fully in one section and then referenced in other sections, as appropriate. When the metabolic pathway or interaction data results in recom- mendations for dosage adjustments, contraindications, or warnings (e. Refer to the guidance for industry on labeling (32) for more information on presenting drug interaction information in labeling. In certain cases, information based on clinical studies not using the labeled drug can be described with an explanation that similar results may be expected for that drug. The information provided by these studies needs to be appreciated and understood by prescribers and utilized in individualizing pharmacotherapy. An integrated approach to studying and evaluating drug-drug interactions during the drug development and regulatory review process and incorporating language into labeling has been described. This integrated approach should be based on good under- standing and utilization of the primary question, our willingness to rely on in vitro and in vivo pharmacokinetic and pharmacodynamic data, and our understanding of the degree to which an observed change in substrate mea- sures caused by an interacting drug is or is not clinically important. In recent years, understanding the metabolic disposition and identifying the potential for metabolic drug-drug interactions such as inhibition and induction of enzymes has become an integral part of the drug development process.

Old infarcts tend to be pale ofloxacin 400 mg free shipping, shrunken and depressed beneath the surface of the organ buy 400 mg ofloxacin visa. Edema of the surrounding tissues can cause severe problems when the tissue compartment is constrained discount ofloxacin 200 mg line, such as in stroke or compartments of the extremities 200mg ofloxacin free shipping. Bleeding may occur from mucosal surfaces of infarcted organs, such as hematuria (blood in urine), hemoptysis (blood in sputum), and intestinal bleeding from renal, lung, and bowel infarcts respectively. The cardiovascular system is responsible for transporting nutrients, oxygen, carbon dioxide and non- usable metabolic products between various organs in the body. The demands on the cardiovascular system vary greatly during a "normal day" for most of us. Getting out of bed in the morning requires major changes in the cardiovascular system. The lecture will primarily focus on the autonomic nervous system and its role in regulating cardiac function. In addition, some mechanisms responsible for local regulation of blood flow in peripheral vessels will be discussed. After reviewing the basic circuitry for regulating cardiac function, we will ask members of the class to help demonstrate cardiovascular responses to minor physiologic stress. Cardiac output (the volume of blood pumped by the heart per minute) is varied by altering the heart rate or the volume of blood pumped during contraction. The heart rate is controlled by the autonomic nervous system and will be discussed below. The volume of blood pumped during each beat is determined by several factors: 1- The volume of blood delivered to the heart. The autonomic nervous system can regulate delivery of the blood from Cardiac Reflexes - Brian Kobilka, M. The autonomic nervous system can direct cardiac myocytes to change the strength of contraction. When resistance is high, the ventricle cannot empty completely and therefore delivers less volume per contraction. Carotid body and aorticarch baroreceptors detect The autonomic nervous changes in blood pressure. The sympathetic nervous system regulates The sympathetic nervous vascular resistance and system regulates salt and regional blood flow. Large vessels in the abdomen and lower extremities serve as a reservoir for blood. The central nervous system receives information about the performance of the cardiovascular system from several sources. The information is processed at several levels in the central nervous system, but the final integration is accomplished in the dorsal motor nucleus of the vagus, and the vasomotor center located in the medulla and the lower third of the pons. Adjustments in cardiovascular function are made via sympathetic and parasympathetic modulation of the heart rate, and cardiac contractility, as well as sympathetic modulation of arterial resistance, venous capacitance, and renal function. The autonomic nervous system consists of the sympathetic and parasympathetic nervous systems. The vasomotor center controls the sympathetic output to the heart and blood vessels. Parasympathetic innervation of the heart originates in the dorsal motor nucleus of the vagus. Under conditions of normal cardiovascular function both sympathetic and parasympathetic Cardiac Reflexes - Brian Kobilka, M. Modulation of function is accomplished by either increasing or decreasing the basal level of activity to specific organs. Higher levels of central nervous system control over cardiovascular function arise in the cerebral cortex, limbic system and the hypothalamus. These centers exert control over cardiovascular function by modulating the activity of the medullary centers. Some sympathetic control is preserved in patients with low cervical cord transections. Acetylcholine released from postganglionic vagal fibers is rapidly degraded by acetylcholinesterase. Sympathetic nerves originate in the intermediolateral columns of the lower cervical and upper thoracic spinal cord. The preganglionic fibers synapse in the sympathetic ganglia which lie adjacent to the vertebral column. The adrenal medulla is a specialized sympathetic ganglia that releases epinephrine and norepinephrine into the systemic circulation. The neurotransmitter released from the sympathetic nerve terminal is primarily norepinephrine while both epinephrine and norepinephrine are released from the adrenal medulla. As discussed below, specific adrenergic receptor subtypes are more responsive to epinephrine while others are more responsive to norepinephrine. Most of the sympathetic nerves going to the heart either synapse in, or pass through the stellate ganglia (fusion of the last cervical and first thoracic). The right stellate ganglia has a greater effect on heart rate and the left has a greater effect on contractility. Most of the resistance and capacitance vessels to skin, skeletal muscle and viscera are richly innervated by sympathetic nerves. Release of norepinephrine from sympathetic nerve terminals in these vessels leads to vasoconstriction through alpha 1 adrenergic receptors; however, during exercise, circulating epinephrine released from the adrenal medulla activates beta 2 receptors in skeletal muscle vessels leading to dilatation of these vessels. Cerebral, coronary and pulmonary vessels are poorly innervated and are poorly responsive to sympathetic stimulation. Under maximal sympathetic stimulation, blood flow to the brain, heart and lungs is preserved at the expense of other organs. Catecholamines modulate renal blood flow, fluid and electrolyte balance and renin release. Activation of the sympathetic nervous system under severe stress such as the fight or flight response, or strenuous, prolonged physical exertion leads to a generalized release of catecholamines (predominantly norepinephrine) from all sympathetic nerve terminals throughout the body as well as a release of catecholamines from the adrenal gland into the circulation. For example, blood vessels in skeletal muscle dilate to increase blood flow to muscles, while blood vessels in the abdominal viscera constrict, diverting blood from intestines. This organ and tissue specific response to catecholamine release is accomplished by structural and functional diversity in the family of adrenergic receptors that respond to catecholamines. Similar diversity exists in the family of muscarinic receptors that respond to acetylcholine. Muscarinic and adrenergic receptors are structurally and functionally similar plasma membrane receptors that form the interface between the autonomic nervous system and the cardiovascular system. The activated G protein goes on to modulate one or more cellular enzymes or ion channels. There are 9 subtypes of adrenergic receptors (Alpha 1a, b and c, Alpha 2 a, b and c, Beta 1, Beta 2 and Beta 3) and 5 subtypes of muscarinic receptors (m1-m5). The precise physiologic role of each receptor subtype is not yet known; however, some general functional properties can be summarized as follows: 1. Alpha 1 adrenergic receptors are found on smooth muscle cells of both capacitance and resistance vessels.

A drastic treatment for seizures is surgical removal of a brain lobe where seizures orig- inate 400mg ofloxacin fast delivery, and instrument readings during the operation guide surgeons on how much of the brain to remove cheap 200mg ofloxacin visa. Fentanyl is a standard surgical anesthetic buy generic ofloxacin 200mg line, and one study found that the drug can temporarily create seizures in healthy por- tions of the brain order ofloxacin 400mg visa, thereby misleading surgeons about how much they should remove. Like many other drugs, fentanyl has stronger effects on older persons, and dosage should be adjusted accordingly. Just three days of medical dosing can produce enough dependence to cause uncomfortable withdrawal upon sudden stoppage of the drug, an exceptionally short time compared to most opioids. Animal experi- ments indicate that buprenorphine can alleviate fentanyl withdrawal. For the same reason, using fentanyl with other depressants (including alcohol) can be risky. Whether fentanyl causes cancer is unknown, although laboratory tests with one version of the drug yielded no indication of cancer-causing potential. Rats receiving fentanyl have lower fertility rates and bring fewer pregnancies to term, compared to rats not receiving the drug, and those effects occurred at smaller doses than humans typically receive. When fentanyl citrate has been given to pregnant rats, birth defects in their offspring have not been attributed to the drug. The drug passes into a nursing mother’s milk but not in amounts deemed harmful to an infant. It is 50 to 100 times stronger than morphine and is used to knock out wild animals. Sufentanil can lower heart rate and blood pressure, create muscle rigidity, and cause typical unwanted opioid effects such as itching and vomiting. At normal doses su- fentanil can halt breathing, so medical personnel stand by to provide respi- ration assistance when they administer the drug. Researchers examining the results when sufentanil is used in childbirth found no harm to mother or infant. Sufentanil is assumed to pass into the milk of nursing mothers, but the amount is as- sumed harmless to the infant. They are used illicitly to experience heroin sensations and can be 1,000 times stronger than heroin. This quick-acting and long-lasting drug is widely used around the world for legitimate medical purposes. Flunitrazepam is prescribed to treat insomnia and anxiety, to relax muscles, to stop convulsions, and to calm peo- ple. In the 1990s it was Western Europe’s most commonly prescribed calming and sleep-inducing medicine. The drug is administered to treat alcohol with- drawal syndrome, and experimental use in treating depression has found flu- nitrazepam promising. Some unauthorized use of the drug is believed to be for self-medication of depression and low self-esteem. The drug has special- ized usefulness in surgery as a medication given prior to administration of anesthesia, and its tendency to reduce pressure inside the eyeball can avert the rise caused by the anesthetic succinylcholine (important if patients are at risk for glaucoma). In hospice care where doses can be higher and more fre- quent than normal, flunitrazepam has reduced nausea and vomiting from can- cer chemotherapy. Actions are similar to those of diazepam, but flunitrazepam is 7 to 10 times stronger. Nonetheless, compared to other benzodiazepine class drugs an over- dose of flunitrazepam does not seem more poisonous, nor does flunitrazepam appear more prone to cause medical crises. The drug may cause euphoria, raise self-esteem, and give a 168 Flunitrazepam sense of power in users while at the same time decreasing fear. Such effects may promote violence in a person who is already prone to such conduct, particularly when the substance is combined with alcohol. Users are sometimes unable to remember what happened while they were under flunitrazepam’s influence. Immediate effects aside, researchers have documented that people still experience trouble when doing laboratory mem- ory tests 10 hours after taking a medical dose of the drug, a dose that may be much lighter than some abusers take. Many other benzodiazepine class drugs cause memory trouble as well, although their effect is less publicized than flunitrazepam’s. Flunitrazepam can slow reaction times, reduce ability to pay attention to tasks, and leave people too woozy and discoordinated to drive a car safely. Difficulty in driving has been demonstrated in simulations and in an instru- mented automobile actually driven for several miles the day after drivers took a nighttime dose. In experiments (including a test of potential drug effects on shift workers) people took various sleep aids at bedtime; flunitrazepam harmed persons’ ability to move their limbs the next day. Such effects appear to be dose-related; an experiment using much smaller doses found little or no impact on performance the next day. Abuse of the drug has become a concern among public health authorities in several countries. State gov- ernments have begun reclassifying the substance as Schedule I, certifying it as having no medical value and allowing anyone possessing it to be prose- cuted under state law. In the 1990s law enforcement agencies declared flunitrazepam to be a date rape drug, allowing men to commit sexual assault against unresisting victims who have foggy or even no memory of the circumstances. In a survey of 53 women who willingly used flunitrazepam, 10% said they were afterward as- saulted physically or sexually. When 66 other “flunitrazepam users” described the tablet, many descriptions were of some other drug even though the people believed they had taken flunitrazepam. Untoward events may be real, but the identity of an involved drug may be less certain than law enforcement officials say. A student of the topic found that from 1994 to 1998 a nationwide total of “at least” 26 sexual assaults “po- tentially involved” the drug. One laboratory conducted a two-year study of 1,179 urine specimens from sexual assault victims in 49 states, specimens se- lected because of suspicion that some drug was involved—and thereby more likely to have positive results than if samples were chosen randomly from sex crime cases. The same study reported that as of 1999 utilization of those two drugs seemed to be waning. Flunitrazepam’s legal manufacturer has offered to provide free and definitive analysis of samples submitted by medical and law enforcement personnel. Researchers at the Uni- versity of Miami report that detection of flunitrazepam in urine samples is easy and that, in contrast to ambiguous results from sex crime investigations, flunitrazepam had been confirmed in “up to” 10% of drunk driving cases in 1995 and 1996 in Miami-Dade County, Florida, but plummeted after the drug became Schedule I under state law in 1997. Despite hype about flunitrazepam, a review article published in 1997 noted absence of evidence that the substance’s actions differ from those of other drugs in the benzodiazepine class. Flunitrazepam is simply a very strong ben- zodiazepine, and its potency may have much to do with stories told about it. To produce similar drug effects, a small amount of flunitrazepam may be about equal to a large amount of some other benzodiazepine. A person’s body can develop dependence with fluni- trazepam, resulting in a withdrawal syndrome if dosage stops. Withdrawal symptoms are similar to those with other benzodiazepine class substances. When re- searchers cut off the drug supply to dependent monkeys they became agitated and peevish, had tremors and poor control of muscles, and sometimes vom- ited and ran a fever.